The invention relates to a method of verifying the synthesis of organic molecules using nuclear magnetic resonance spectroscopy. The method is particularly suited for use in libraries of compounds produced by combinatorial chemistry.
A large number of new organic compounds can be automatically synthesized from a smaller number of molecular structures using the techniques of combinatorial chemistry. These molecular structures contributing to the product are assigned a molecular structure code. Methods have been proposed for the subsequent verification of the success or failure of the synthesis (see for example “COMBINATORIAL” by A. W. Czarnik, Analytical Chemistry News & Features, pages 378 A to 386 A, 1 Jun. 1998).
Combinatorial chemistry methods aim at synthesizing compounds using a small number of chemical reactants in all combinations defined by a given reaction scheme to obtain a large number of well-defined products. NMR methods can be used to verify synthesis of these products with high throughput. The assessment of the measured NMR spectra has been conventionally carried out “manually” and mainly intuitively by highly specialized chemists and has also been based on relatively inaccurate model calculations.
The purity control and structure verification of compound libraries produced by automated synthesis and combinatorial chemistry both play an essential role in the success of medicinal chemistry programs. High performance liquid chromatography (HPLC), mass spectrometry (MS) and liquid chromatography-mass spectrometry (LC-MS) techniques are generally accepted as the most appropriate means of characterization. Although these analytical methods are fast and easy to automate, they do not provide sufficient structural and quantitative data about the desired products.
Nuclear magnetic resonance (NMR) spectroscopy is the most informative analytical technique and is widely applied in combinatorial chemistry. However, an automated interpretation of the NMR spectral results is difficult. The interpretation can usually be supported by use of spectrum calculation and structure generator programs. Automated structure validation methods rely on 13C NMR signal comparison using molecular structure/molecular-spectra correlated databases or shift prediction methods.
In view of these aspects of prior art, it is the object of the present invention to present an NMR method which permits rapid, reproducible and reliable verification of a large number of molecular compounds produced by combinatorial chemistry.